This Small Business Innovation Research Phase I project at Azano Pharmaceuticals, Inc. will help establish the technical and commercial feasibility of a novel treatment for systemic lupus erythematosus (SLE). SLE is a chronic inflammatory disease of humans that affects multiple organ systems. Perhaps the most severely affected organ is the kidney, and lupus nephritis (LN) is a major cause of morbidity and mortality in patients with SLE. There is no effective cure, and while standard therapies can ameliorate symptoms in some patients, they are nonspecific, inefficient, and associated with debilitating side effects. Consequently, new therapeutic approaches are needed for the treatment of LN in SLE patients. The new therapeutic treatment that this application will develop is based on the demonstration that C-reactive protein (CRP), a classical acute phase serum protein, reverses lupus nephritis with a onetime injection in multiple mouse models. CRP-mediated suppression of disease requires FcgRI and macrophages. A CRP mutant, Y175L, has been derived that binds strongly to FcgRI but lacks binding to FcgRII. The hypothesis is that wild-type CRP (wtCRP) binding of both inhibitory receptor FcgRIIb and activating receptor FcgRI on target macrophages attenuates the magnitude of the effector cell response. Thus, the lack of inhibitory receptor binding by Y175L could result in a more specific activity and significantly increase the potency of CRP therapy for LN. The goal of this proposal is to evaluate the ability of Y175L to prevent and reverse lupus nephritis and to determine its viability as a drug candidate for further preclinical development alongside wtCRP. WtCRP and Y175L will be evaluated in vivo for their ability to ameliorate development of disease symptoms in the murine (NZB x NZW)F1 model, which resembles human SLE. Drugs will be tested in both prophylactic and therapeutic protocols. Drug efficacy will be monitored by delay of proteinuria, reversal of nephritis, and extended survival as endpoints. The results of this study will determine the best drug candidate(s) for further preclinical and clinical development. Because CRP treats the cause of lupus nephritis, this therapeutic approach should be more effective than other biological therapies that only target the side effects of renal flares. Ultimately, this work will develop a new therapeutic option for lupus nephritis patients based on a specific mechanism that may be superior to current treatments. PUBLIC HEALTH RELEVANCE: This work will develop a new therapeutic option for lupus nephritis in SLE patients, based on a specific mechanism that may be superior to current therapies.